Tao Tao, Yang Xiaomei, Qin Qiong, Shi Wen, Wang Qiqi, Yang Ying, He Junqi
Department of Biochemistry and Molecular Biology, Capital Medical University, Beijing 100069, China.
Beijing International Cooperation Base for Science and Technology on China-UK Cancer Research, Beijing 100069, China.
Int J Mol Sci. 2017 Jan 12;18(1):5. doi: 10.3390/ijms18010005.
Cervical cancer is one of the most common female malignancies, and cisplatin-based chemotherapy is routinely utilized in locally advanced cervical cancer patients. However, resistance has been the major limitation. In this study, we found that Na⁺/H⁺ Exchanger Regulatory Factor 1 (NHERF1) was downregulated in cisplatin-resistant cells. Analysis based on a cervical cancer dataset from The Cancer Genome Atlas (TCGA) showed association of NHERF1 expression with disease-free survival of patients received cisplatin treatment. NHERF1 overexpression inhibited proliferation and enhanced apoptosis in cisplatin-resistant HeLa cells, whereas NHERF1 knockdown had inverse effects. While parental HeLa cells were more resistant to cisplatin after NHERF1 knockdown, NHERF1 overexpression in CaSki cells promoted cisplatin sensitivity. Overexpression and knockdown studies also showed that NHERF1 significantly inhibited AKT and extracellular signal-regulated kinase (ERK) signaling pathways in cisplatin-resistant cells. Taken together, our results provide the first evidence that NHERF1 can sensitize cisplatin-refractory cervical cancer cells. This study may help to increase understanding of the molecular mechanisms underlying cisplatin resistance in tumors.
宫颈癌是最常见的女性恶性肿瘤之一，基于顺铂的化疗通常用于局部晚期宫颈癌患者。然而，耐药性一直是主要限制因素。在本研究中，我们发现钠氢交换调节因子1（NHERF1）在顺铂耐药细胞中表达下调。基于癌症基因组图谱（TCGA）的宫颈癌数据集分析显示，NHERF1表达与接受顺铂治疗患者的无病生存期相关。NHERF1过表达抑制顺铂耐药的HeLa细胞增殖并增强其凋亡，而NHERF1敲低则产生相反的效果。虽然敲低NHERF1后亲本HeLa细胞对顺铂更耐药，但在CaSki细胞中过表达NHERF1可提高顺铂敏感性。过表达和敲低研究还表明，NHERF1在顺铂耐药细胞中显著抑制AKT和细胞外信号调节激酶（ERK）信号通路。综上所述，我们的结果首次证明NHERF1可使顺铂难治性宫颈癌细胞敏感化。本研究可能有助于增进对肿瘤顺铂耐药潜在分子机制的理解。
